Anti-viral cyclic compound

Abstract

The present invention relates to novel cyclic peptides. These peptides bind to conserved sites on viral proteins, particularly the SARS-CoV-2 spike protein, and thus the peptides may be useful for neutralizing SARS-CoV-2 variants. Accordingly, the present invention also relates to the medical use of these peptides.

Description

Technical Field

[0001] The present invention relates to novel cyclic peptides. These peptides bind to conserved sites on viral proteins, particularly the SARS-CoV-2 spike protein, and thus the peptides may be useful for neutralizing SARS-CoV-2 variants. Accordingly, the present invention also relates to the medical use of these peptides.

Background Art

[0002] Cell entry by SARS-CoV-2 is mediated by a membrane spike glycoprotein that recognizes the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of host cells (Jackson et al., Nat. Rev. Mol. Cell Biol. 23, 3-20, 2022). The spike protein is a trimeric protein consisting of a helical stalk domain (S2) covered by the S1 head at the apex. The S1 domain is responsible for host cell receptor binding, while S2 promotes subsequent membrane fusion. Infection is associated with proteolytic cleavage at the S1 / S2 and S2' sites by host cell proteases. Overall, this results in the release of the S1 unit from the S2 stalk and subsequent conformational changes in S2 necessary for fusion of the viral and host membranes. In the prefusion state, each monomer of the S1 domain of the spike protein consists of a receptor-binding domain (RBD) and an N-terminal domain (NTD). The spike protein can exist in either a closed state where all RBDs are "down" and inaccessible for receptor binding, or an open state where at least one of the RBDs is in the "up" conformation and thus accessible for ACE2 binding (Wrapp, D. et al. Science 367, 1260-1263, 2020).

[0003] The SARS-CoV-2 spike protein exposed on the viral membrane is a promising target for antibodies as a therapeutic intervention for COVID-19. Isolation of human antibodies from convalescent donors has yielded many potent neutralizing antibodies, some of which are in clinical trials. Most of these antibodies target sites on the RBD that result in direct interference with ACE2 binding, although distinct neutralizing sites on the RBD have also been identified. These SARS-CoV-2 neutralizing antibodies that target the spike RBD have been classified into four classes in the literature.

[0004] Class 1 antibodies bind to the receptor-binding motif (RBM) only in the "up" RBD conformation. Class 2 antibodies also bind to the RBM at an adjacent site and can bind in both the "up" and "down" states of the RBD. Both classes have been found to be poorly conserved among coronaviruses and target sites that have been shown to lose activity against different variants of SARS-CoV-2. Cross-neutralizing antibodies of classes 3 and 4 target more conserved sites on the RBD outside of the ACE2-binding site, and these two binding sites have also been described as the S309 proteoglycan site (class 3) and the CR3022 cryptic site (class 4). The proteoglycan S309 site is accessible in both the "down" and "up" states. Neutralizing antibodies that target this site, such as S309 and C135, do not compete for ACE2 binding and thus have been found to have different mechanisms of action. The CR3022 cryptic site, located on the opposite side of the S309 site, is derived from the SARS-CoV neutralizing antibody CR3022, which has been found to bind to the SARS-CoV-2 RBD but is non-neutralizing. This site can only be accessed in the "up" conformation of the RBD. For CR3022, it has been found that not all antibodies that bind to this site neutralize viral infection, and those that do are proposed to sterically interfere with ACE2 binding based on their resolved structures. Receptor binding occurs through interaction with the RBD, but neutralizing antibodies that target the NTD have also been discovered. These antibodies are most likely to stabilize the prefusion state of the spike and prevent the conformational changes necessary for membrane fusion.

[0005] Current antibodies in clinical trials are greatly affected by mutations occurring in new variants. In a recent study, it was found that 6 out of 9 antibodies in clinical trials lose their activity against the Omicron variant (Planas, D. et al., 2021, doi: 10.1101 / 2021.12.14.472630). The least affected antibody, Sotrovimab, derived from S30914, was found to have a 1 / 3 reduction in efficacy against Omicron. Two other antibodies, Cilgavimab (class 2) and Adintrevimab (epitope between classes 1 and 4), were found to have a 1 / 20 reduction in activity. This shows the difficulty of antibody development against mutant viruses and the need to target conserved epitopes.

[0006] The production of antibodies requires a lot of time and effort, and their storage, transportation, and administration to subjects are affected by various factors. More stable, easier-to-manufacture, and cost-effective alternatives are highly attractive.

[0007] As a result, improved treatments, prevention, or remission of viral infections are needed. Antiviral substances with improved stability are needed. Antiviral substances with a more robust activity profile are needed. For example, substances that can neutralize SARS-CoV-2 by a new mechanism of action, through modulation of the conformational dynamics of the viral spike protein, are needed. Substances that can modulate the conformational dynamics of the viral spike protein are needed. SUMMARY OF THE INVENTION

[0008] The present invention relates to a compound of general formula (I):

Chemical formula

[0009] In a preferred embodiment, the linker contains 1 to 12 optionally substituted backbone atoms selected from carbon, nitrogen, oxygen and sulfur, and any substitution may be =O, halogen, C1-4 hydrocarbon, C1-4 acyl, C1-4 alkoxy, -C(=O)-oligopeptide, -SH, -S-(C1-4 hydrocarbon), -NH2, -NH-(C1-4 hydrocarbon), -NH-(C1-4 acyl), -N-(C1-4 hydrocarbon)2, -N-(C1-4 acyl)2, an amino acid side chain, or a targeting moiety. Preferably, the linker has the general formula (L1):

Chemical formula

Chemical formula

[0010] Preferably, the peptide is an oligopeptide having 13 to 17 amino acid residues, the first amino acid is arginine, histidine or lysine, preferably arginine, the seventh amino acid is isoleucine or leucine, preferably isoleucine, and the twelfth amino acid is isoleucine or leucine, preferably leucine. In some embodiments, the peptide may contain a sequence represented by any one of SEQ ID NOs: 1 to 30, and up to 6 positions may be substituted by another amino acid. Preferably, the peptide has 15 amino acid residues, and / or the peptide contains a sequence represented by any one of SEQ ID NOs: 1 to 2, and / or the linker has any one of the general formulas (L4a) to (L4h), and / or X is NH. In a preferred embodiment, the peptide is an oligopeptide having a length of 15 to 17 amino acids, preferably 15 amino acids, and having 5, 4, 3, 2, or 1 amino acid substitutions and is represented by SEQ ID NO: 1.

[0011] In a highly preferred embodiment, the compound is cyclic peptide 1 or a salt thereof. [Chemical formula]

[0012] Compositions comprising a compound defined above and a pharmaceutically acceptable excipient are also provided. The compound or the composition for use as a medicament is also provided. Preferably, the medicament is for treating a viral infection, preferably a coronavirus infection, more preferably a SARS-CoV-2 infection.

[0013] In vitro, in vivo, or ex vivo methods for modulating the conformational dynamics of a viral spike protein are also provided, the method comprising contacting the viral spike protein with a compound or composition defined above. A method for treating a viral infection is also provided, the method comprising administering a compound or composition defined above to a subject.

Mode for Carrying Out the Invention

[0014] The inventors have found that some oligopeptides have high affinity for viral proteins. It has been found that the identity of some residues within these oligopeptides has a great influence on protein binding. Accordingly, the present invention provides a compound of general formula (I):

Chemical formula

[0015] The salts of the compounds according to the invention are preferably pharmaceutically acceptable salts. Such salts include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn, and salts of organic bases such as N,N'-diacetyl ethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, alpha-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine and the like. Such salts also include amino acid salts, for example, glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine and the like. Such salts may include, where appropriate, acid addition salts, which are, for example, sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides such as HCl salts or HBr salts, acetates, trifluoroacetates, tartrates, maleates, citrates, succinates, palmitates, methanesulfonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Preferred salts are HCl salts, formates, acetates and trifluoroacetates. More preferred salts are HCl salts and trifluoroacetates, and most preferred is the HCl salt.

[0016] The compounds according to the invention can be hydrates or solvates. In the context of the present invention, hydrates refer to solvates in which the solvent is water. The term solvate as used herein refers to the crystalline form of a substance containing a solvent. Solvates are preferably pharmaceutically acceptable solvates, which may be hydrates or may contain other solvents for crystallization such as alcohols, ethers and the like.

[0017] [Peptide moiety] The peptide is an oligopeptide having 13 to 17 amino acid residues. The first amino acid is preferably arginine, lysine, histidine, leucine, isoleucine or valine. The seventh amino acid is preferably isoleucine, leucine or valine. The twelfth amino acid is preferably isoleucine, leucine or valine. In a preferred embodiment, the peptide is an oligopeptide having 13 to 17 amino acid residues. The first amino acid is arginine, lysine, histidine, leucine, isoleucine or valine. The seventh amino acid is isoleucine, leucine or valine. The twelfth amino acid is isoleucine, leucine or valine.

[0018] The amino acid residues included in the peptide can be any amino acids not limited to those constituting naturally occurring proteins. As used herein, the use of the term oligopeptide should be construed to include, in addition to oligopeptides that are naturally occurring proteinaceous amino acids in which each residue is linked to its adjacent group via a backbone amide bond, non-natural amino acids, peptide mimetics, peptides containing non-conventional linkages, and other modifications. This includes alkylated bonds, reverse bonds, or other types of bonds, such as esters, triazoles, carbamates, ureas, thioureas, imides, imines, halogenated bonds, alpha-halogenated bonds, oligopeptides containing ketones, or oligopeptides containing beta-amino acids, other extended amino acids, or peptoids in which the side chain of the residue is attached to the backbone amide bond rather than the corresponding alpha carbon atom.

[0019] As used herein, the term "amino acid" should be construed as any moiety that can form the residues in a polypeptide as previously defined. Peptides may contain amino acids of any chirality, such as L-amino acids, D-amino acids, or mixtures thereof. In most cases, an amino acid is preferably a molecular acid characterized by a carboxylic acid, and the amino acid is characterized by an amine at the alpha-carbon adjacent to the carboxylic acid. However, this amine may be further removed from the carboxylic acid. The amino acids that make up the most common naturally occurring proteins, along with their three-letter abbreviations and one-letter codes, are as follows: Alanine (Ala, A), Arginine (Arg, R), Asparagine (Asn, N), Aspartic acid (Asp, D), Cysteine (Cys, C), Glutamic acid (Glu, E), Glutamine (Gln, Q), Glycine (Gly, G), Histidine (His, H), Isoleucine (Ile, I), Leucine (Leu, L), Lysine (Lys, K), Methionine (Met, M), Phenylalanine (Phe, F), Proline (Pro, P), Serine (Ser, S), Threonine (Thr, T), Tyrosine (Tyr, Y), Tryptophan (Trp, W), Valine (Val, V). In the latter part of this specification, where indicated, X is further used for L-3,4-dihydroxy-phenylalanine and Z is further used for pentafluorophenylalanine. Naturally occurring amino acids are also called natural amino acids. Natural amino acids often constitute proteins, which means they are used by organisms in protein biosynthesis. In some cases, natural amino acids may not constitute proteins either. A natural amino acid is an amino acid that can be found in nature without further restricting its role or function.

[0020] The amino acids contained in the peptide are radicals, and it should be understood that at least one hydrogen of the amine is absent and one hydroxyl moiety of the carboxylic acid moiety is absent. This is consistent with, for example, the three-letter notation of H-Gly-OH, where the first H represents the H on the amine of glycine and OH represents the hydroxyl moiety of the carboxylic acid of glycine. In this regard, X can be regarded as substituting the H- or -OH of the terminal amino acid of the peptide contained in the compound according to the present invention. Similarly, the linker substitutes the H- or -OH of the other terminal amino acid of the peptide. Preferably, X substitutes -OH and the linker substitutes H-. In other words, preferably, X is the C-terminus and the linker is the N-terminus. It should be understood that when used throughout this specification, the terminus may indicate the terminus of a moiety and does not necessarily indicate the terminus of the entire compound. In fact, the compounds according to the present invention are generally macrocyclic and can be said to contain no actual termini.

[0021] In a preferred embodiment, the peptide is an oligopeptide having 13 to 17 amino acid residues, and these amino acid residues are L-amino acids or D-amino acids or mixtures thereof. More preferably, the peptide is an oligopeptide having 13 to 17 amino acid residues, and the amino acid residues are L-amino acids. Preferably, the peptide is an oligopeptide having 13 to 17 amino acid residues, and the amino acid residues are amino acids constituting naturally occurring proteins or pentafluorophenylalanine or L-DOPA. Preferably, the peptide is an oligopeptide having 13 to 17 amino acid residues, and the amino acid residues are amino acids constituting naturally occurring proteins. More preferably, the peptide is an oligopeptide having 13 to 17 amino acid residues, and its amino acid residues are L-amino acids or D-amino acids or mixtures thereof and are amino acids constituting naturally occurring proteins. Most preferably, the peptide is an oligopeptide having 13 to 17 amino acid residues, and the amino acid residues are L-amino acids and are amino acids constituting naturally occurring proteins.

[0022] Amino acids are often characterized by the nature of their side chains. Amino acids considered to be basic amino acids are lysine, arginine, and histidine. Amino acids considered to be acidic amino acids are aspartic acid, glutamic acid, and tyrosine. Amino acids considered to be polar uncharged amino acids are serine, threonine, cysteine, asparagine, and glutamine. Amino acids regarded as hydrophobic amino acids are alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, proline, and tryptophan. Proline is considered to be an amino acid with a constrained conformation. Glycine is achiral but can be considered as both D-amino acid and L-amino acid. Further moieties can be conjugated to the side chains of some amino acid residues, for example, a protecting group, an alkyl group, for example, a C1-6 alkyl group, or a further amino acid residue, for example, glycine.

[0023] In embodiments of the present invention, the peptide may be included in a larger oligopeptide, for example, when the linker contains a further amino acid residue. It is further understood that the oligopeptide optionally features protecting groups such as t-butyl carbamate, 9-fluorenylmethyl carbamate, benzyl carbamate, benzyl ester, t-butyl ester, methyl ester, or other protecting groups. Preferably, the amino acid residues are not protected in the compounds according to the present invention.

[0024] The peptide has 13 to 17 amino acid residues. That is, the peptide has 13, 14, 15, 16, or 17 amino acid residues. These amino acid residues are the amino acid residues that form the backbone of the oligopeptide. For example, when linked to the side chain of an amino acid residue contained in the backbone of the oligopeptide, additional amino acid residues may be present. In some embodiments, the peptide has 13 amino acid residues. In some embodiments, the peptide has 14 amino acid residues. In some embodiments, the peptide has 15 amino acid residues. In some embodiments, the peptide has 16 amino acid residues. In some embodiments, the peptide has 17 amino acid residues.

[0025] In some embodiments, the peptide has 13 to 16 amino acid residues. In some embodiments, the peptide has 13 to 15 amino acid residues. In some embodiments, the peptide has 13 to 14 amino acid residues. In some embodiments, the peptide has 14 to 17 amino acid residues. In some embodiments, the peptide has 14 to 16 amino acid residues. In some embodiments, the peptide has 14 to 15 amino acid residues. In some embodiments, the peptide has 15 to 17 amino acid residues. In some embodiments, the peptide has 15 to 16 amino acid residues. In some embodiments, the peptide has 16 to 17 amino acid residues. Preferably, the peptide has 14 to 16 amino acid residues, more preferably 14 to 15 amino acid residues, and most preferably 15 amino acid residues.

[0026] Systematic experimental studies have revealed that specific amino acid residues strongly contribute to the binding properties of the compounds according to the present invention. Good properties were found when the first amino acid is arginine, lysine, histidine, leucine, isoleucine or valine, the seventh amino acid is isoleucine, leucine or valine, and the twelfth amino acid is isoleucine, leucine, or valine. When counting the amino acid residues, preferably the counting starts from the position opposite to X. This X is as shown in the general formula (I). In a highly preferred embodiment, the counting starts at the N-terminus of the peptide. The counting is continuous.

[0027] In a preferred embodiment, the peptide is an oligopeptide having 13 to 17 amino acid residues, the first amino acid is arginine, histidine or lysine, preferably arginine, the seventh amino acid is isoleucine or leucine, preferably isoleucine, and the twelfth amino acid is isoleucine or leucine, preferably leucine.

[0028] In some preferred embodiments, the first amino acid is arginine, lysine or histidine, most preferably arginine. In some preferred embodiments, the first amino acid is leucine, isoleucine or valine, most preferably isoleucine. In a highly preferred embodiment, the first amino acid is arginine or isoleucine.

[0029] In some preferred embodiments, the seventh amino acid is isoleucine. In some preferred embodiments, the seventh amino acid is valine. In a highly preferred embodiment, the seventh amino acid is isoleucine or valine.

[0030] In some preferred embodiments, the twelfth amino acid is leucine. In some preferred embodiments, the twelfth amino acid is valine. In a highly preferred embodiment, the twelfth amino acid is leucine or valine.

[0031] When the first amino acid is arginine, lysine or histidine, the seventh amino acid is preferably isoleucine or leucine, more preferably isoleucine. When the first amino acid is arginine, lysine or histidine, the twelfth amino acid is preferably isoleucine or leucine, more preferably leucine.

[0032] When the first amino acid is leucine, isoleucine or valine, the seventh amino acid is preferably isoleucine or leucine, more preferably leucine. When the first amino acid is leucine, isoleucine or valine, the twelfth amino acid is preferably valine.

[0033] Here, when an oligopeptide is provided, it can be obtained from a commercial source or by isolating it from natural products. The oligopeptide can be obtained by isolation from digests of larger proteins. Preferably, the oligopeptide is of synthetic origin. A preferred method for oligopeptide synthesis is solid-phase peptide synthesis (SPPS), which is well known to those skilled in the art. The advantages of obtaining short peptides by SPPS are ease of synthesis, low component costs, synthesis speed, and the possibility of automation using a synthesis robot, synthesizer, semi-automatic synthesizer, or automatic synthesizer. SPPS strategies known in the art enable modification of both the N-terminus and C-terminus, such as alkylation, amidation, or labeling. Those skilled in the art will understand that when an amino acid is referred to as having a particular characteristic, it generally refers to the side chain of the amino acid. As a non-limiting example, when phenylalanine is referred to as a hydrophobic amino acid, its amine moiety and its carboxylic acid portion are not considered.

[0034] In a preferred embodiment, the peptide comprises a sequence represented by any one of SEQ ID NOs: 1 to 30, and up to six positions may be substituted with another amino acid. Preferably, the peptide does not contain additional amino acid residues. In some embodiments, up to five positions can be substituted with another amino acid, and this substitution preferably includes substitutions at residues selected from 4, 5, 6, 9, 14, and 15, more preferably substitutions at residues selected from 4, 5, 6, 14, and 15. Systematic studies have revealed that these positions of the compounds according to the present invention are highly resistant to mutations. In some embodiments, up to five positions can be substituted with another amino acid, and this substitution preferably includes substitutions at residue 14 and / or 15, more preferably substitutions at both residues 14 and 15.

[0035] In some embodiments, up to four positions can be substituted with another amino acid, and this substitution preferably includes substitutions at residues selected from 4, 5, 6, 14, and 15. In some embodiments, up to four positions can be substituted with another amino acid, and this substitution preferably includes substitutions at residue 14 and / or 15, more preferably substitutions at both residues 14 and 15.

[0036] In some embodiments, up to three positions can be substituted with another amino acid, and this substitution preferably includes substitutions at residues selected from 4, 5, 6, 14, and 15. In some embodiments, up to three positions can be substituted with another amino acid, and this substitution preferably includes substitutions at residue 14 and / or 15, more preferably substitutions at both residues 14 and 15.

[0037] In some embodiments, up to two positions can be substituted with another amino acid, and this substitution preferably includes substitutions at residues selected from 4, 5, 6, 14, and 15. In some embodiments, up to two positions can be substituted with another amino acid, and this substitution preferably includes substitutions at residue 14 and / or 15, more preferably substitutions at both residue 14 and 15.

[0038] In some embodiments, a position can be substituted with another amino acid, and this substitution is preferably a residue selected from 4, 5, 6, 14, and 15, preferably selected from 14 and 15. Suitable SEQ ID NOs. for the peptide are shown below. The sequences are artificial.

[0039] The following substitutions are referred to herein as preferred substitutions. In these preferred substitutions, the one-letter amino acid code is used, and the additional definition of Z refers to pentafluorophenylalanine (2-amino-3-(pentafluorophenyl)propanoic acid), and X refers to L-DOPA (L-3,4-dihydroxy-phenylalanine). When the 1st position is substituted with another amino acid, it is preferably substituted with Z, Q, L, R, or C, more preferably with Q, K, or C, and most preferably with K. When the 2nd position is substituted with another amino acid, it is preferably substituted with Z, R, or C, more preferably with C. When the 3rd position is substituted with another amino acid, it is preferably substituted with A, L, Z, X, S, T, N, Q, H, L, R, P, or C, more preferably with L, S, T, N, K, R, or C, and most preferably with C. When the 4th position is substituted with another amino acid, it is preferably substituted with A, Z, R, P, or C, more preferably with Z, P, or C, and most preferably with C. When the 5th position is substituted with another amino acid, it is preferably substituted with A, F, Y, X, W, S, N, H, R, D, E, or C, more preferably with A, Y, X, W, S, N, H, or C, and most preferably with X, W, or C. When the 6th position is substituted with another amino acid, it is preferably substituted with A, I, Y, X, W, S, T, Q, H, D, E or C, more preferably substituted with X, W, E or C, and most preferably substituted with C. When the 7th position is substituted with another amino acid, it is preferably substituted with V or I, and most preferably substituted with V. When the 8th position is substituted with another amino acid, it is preferably substituted with I. When the 9th position is substituted with another amino acid, it is preferably substituted with I, F, Z or W, more preferably substituted with Z or W, and most preferably substituted with Z. When substituted with another amino acid at the 10th position, it is preferably substituted with G. When substituted with another amino acid at the 11th position, it is preferably substituted with S or C. When the 12th position is substituted with another amino acid, it is preferably substituted with V, I, L, Z, T, R or C, more preferably substituted with V, I, Z or R, and most preferably substituted with V or I. When the 13th position is substituted with another amino acid, it is preferably substituted with W. When the 14th position is substituted with another amino acid, it is preferably substituted with G, A, V, Y, X, S, T, Q, H, D, E or C, more preferably substituted with G, A, S, T, Q, H, D, E or C, even more preferably substituted with G, H, D or E, and most preferably substituted with E. When the 15th position is substituted with another amino acid, it is preferably substituted with A, V, I, L, F, Z, Q, H, R, E, P or C, more preferably substituted with A, V, I, L, Q, E or P, even more preferably substituted with I, L, Q or E, and most preferably substituted with I or L.

[0040] The above-mentioned preferred substitutions are preferably the substitutions of SEQ ID NO: 1. In a highly preferred embodiment, the peptide is an oligopeptide having 15 to 17 amino acids, preferably 15 amino acids, contains SEQ ID NO: 1, and may have the above-mentioned preferred substitutions, preferably up to 5 of the above-mentioned preferred substitutions, more preferably up to 4, even more preferably up to 3, even more preferably up to 2, and most preferably only 1 of the above-mentioned preferred substitutions.

[0041] In a preferred embodiment, the peptide is an oligopeptide represented by SEQ ID NO: 1, and the above-mentioned preferred substitutions are made only at positions 2, 3, 4, 5, 6, 7, 9, 12, 14 or 15, more preferably only at positions 2, 3, 5, 6, 7, 12, 14 or 15, even more preferably only at positions 5, 12 or 14, and most preferably only at positions 12 or 14.

[0042] In a highly preferred embodiment, the peptide is an oligopeptide represented by SEQ ID NO: 1, and the above-mentioned preferred substitutions are made only at positions 2, 3, 4, 5, 6, 7, 9, 12, 14 or 15, more preferably only at positions 2, 3, 5, 6, 7, 12, 14 or 15, even more preferably only at positions 5, 12 or 14, and most preferably only at positions 12 or 14.

[0043] In a highly preferred embodiment, the peptide is an oligopeptide represented by SEQ ID NO: 1 that has a length of 15 to 17 amino acids, preferably 15 amino acids in length, and has 5, 4, 3, 2, or 1 substitution. When the 1st position is substituted with another amino acid, it is preferably substituted with Z, Q, L, or C, more preferably with Q, K, or C, and most preferably with K. When the 2nd position is substituted with another amino acid, it is preferably substituted with Z or C, more preferably with C. When the 3rd position is substituted with another amino acid, it is preferably substituted with A, L, Z, X, S, T, N, Q, H, L, R, or C, more preferably with L, S, T, N, K, R, or C, and most preferably with C. When the 4th position is substituted with another amino acid, it is preferably substituted with A, Z, P, or C, more preferably with Z, P, or C, and most preferably with C. When the 5th position is substituted with another amino acid, it is preferably substituted with A, F, Y, X, W, S, N, H, R, D, or C, more preferably with A, Y, X, W, S, N, H, or C, and most preferably with X, W, or C. When the 6th position is substituted with another amino acid, it is preferably substituted with A, I, Y, X, W, S, T, H, D, E, or C, more preferably with X, W, E, or C, and most preferably with C. When the 7th position is substituted with another amino acid, it is substituted with V. The 8th position is not substituted. When the 9th position is substituted with another amino acid, it is preferably substituted with F, Z, or W, more preferably with Z or W, and most preferably with Z. When the 10th position is substituted with another amino acid, it is preferably substituted with C. When the 11th position is substituted with another amino acid, it is preferably substituted with C. When the 12th position is substituted with another amino acid, it is preferably substituted with V, I, Z, T, R, or C, more preferably with V, I, Z, or R, and most preferably with V or I. The 13th position is not substituted. When the 14th position is substituted with another amino acid, it is preferably substituted with G, A, Y, X, S, T, Q, H, D, E, or C, more preferably with G, A, S, T, Q, H, D, E, or C, even more preferably with G, H, D, or E, and most preferably with E. When the 15th position is substituted with another amino acid, it is preferably substituted with A, V, I, L, Z, Q, H, R, E, P, or C, more preferably with A, V, I, L, Q, E, or P, even more preferably with I, L, Q, or E.Most preferably substituted with I or L, the substitution preferably being only at positions 2, 3, 4, 5, 6, 7, 9, 12, 14 or 15, more preferably only at positions 2, 3, 5, 6, 7, 12, 14 or 15, even more preferably only at positions 5, 12 or 14, and most preferably only at positions 12 or 14.

[0044]

Table 1

[0045] SEQ ID NOs: 1 to 13 and 16 to 32 are preferred, as are 33 to 102; SEQ ID NOs: 1 to 13 and 16 to 30 are more preferred, as are 33 to 102. SEQ ID NOs: 1 to 13, 17 to 21, 23 to 26, and 28 to 30 are more preferred, as are 33 to 102. In some embodiments, they are SEQ ID NOs: 1 to 13, and 33 to 102 are also preferred. In some embodiments, they are SEQ ID NOs: 1, 17 to 21, 23 to 26, and 28 to 30. In some embodiments, they are SEQ ID NOs: 1 and 2, and 33 to 102 are also preferred. SEQ ID NO: 1 is most preferred, and 33 to 102 are also preferred.

[0046] The present invention provides an oligopeptide comprising or consisting of the amino acid residues of the peptides defined above. Accordingly, the present invention provides a compound represented by H-peptide-OH. Accordingly, the present invention provides an oligopeptide comprising or consisting of a sequence represented by any one of SEQ ID NOs: 1 to 30. More preferred SEQ ID NOs are SEQ ID NOs: 1 to 13, 17 to 21, 23 to 26, and 28 to 30. In some embodiments, the SEQ ID NO is SEQ ID NOs: 1 to 13. In some embodiments, the SEQ ID NO is SEQ ID NOs: 1, 17 to 21, 23 to 26, and 28 to 30. In some embodiments, the SEQ ID NO is SEQ ID NOs: 1 and 2. SEQ ID NO: 1 is most preferred. The present invention also provides an oligonucleotide comprising a sequence encoding an oligopeptide comprising or consisting of a sequence represented by any one of SEQ ID NOs: 1 to 32, preferably any one of 1 to 13 and 16 to 32. These are preferably peptides consisting of a sequence represented by an SEQ ID NO acetylated at the N-terminus and amidated at the C-terminus.

[0047] Preferred compounds are compounds in which the peptide is an oligopeptide represented by any one of SEQ ID NOs: 1, 33 to 102, more preferably compounds represented by +, ++, +++ or ++++ in Table S4, even more preferably compounds represented by ++, +++ or ++++, even more preferably compounds represented by +++ or ++++, and most preferably compounds represented by ++++ and are SEQ ID NO: 74 or 87.

[0048] [Linker portion] The linker is a linking portion that links the N-terminus and C-terminus of the peptide together with X to form a macrocyclic structure. Accordingly, this macrocyclic structure is formed by the peptide backbone, X, and the linker.

[0049] Preferably, the linker contains 1 to 12 optionally substituted backbone atoms selected from carbon, nitrogen, oxygen, and sulfur, and any substitution can be =O, halogen, C1-4 hydrocarbon, C1-4 acyl, C1-4 alkoxy, -C(=O)-oligopeptide, -SH, -S-(C1-4 hydrocarbon), -NH2, -NH-(C1-4 hydrocarbon), -NH-(C1-4 acyl), -N-(C1-4 hydrocarbon)2, -N-(C1-4 acyl)2, amino acid side chain, or targeting moiety.

[0050] As used herein, a backbone atom is an atom that forms a macrocycle. This is similar to the backbone atoms of a macrocyclic peptide. Preferably, the linker contains 2 to 12, more preferably 3 to 12, even more preferably 4 to 11, 5 to 10, 6 to 9, or 7 to 9 backbone atoms. Most preferably, the linker contains 8 backbone atoms. In some embodiments, the backbone atoms are unsubstituted.

[0051] In preferred embodiments, the backbone atoms are substituted. In particular, any substitution can be =O, halogen, C1-4 hydrocarbon, C1-4 acyl, C1-4 alkoxy, -C(=O)-oligopeptide, -SH, -S-(C1-4 hydrocarbon), -NH2, -NH-(C1-4 hydrocarbon), -NH-(C1-4 acyl), -N-(C1-4 hydrocarbon)2, -N-(C1-4 acyl)2, amino acid side chain, or targeting moiety. Preferably, they can be =O, -C(=O)-oligopeptide, amino acid side chain, or targeting moiety, more preferably =O, -C(=O)-oligopeptide, and amino acid side chain.

[0052] The C1-4 hydrocarbon is preferably acyl, alkyl, cycloalkyl or heterocycloalkyl. Each example of acyl, alkyl, cycloalkyl or heterocycloalkyl is optionally unsaturated and is optionally substituted with halogen, oxy, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, or optionally interrupted by one or more heteroatoms. One skilled in the art will understand that the valences of the atoms should always be satisfied. In this context, heterocycloalkyl should be construed as cycloalkyl interrupted by one or more heteroatoms. The acyl moiety is an alkyl moiety in which the proximal carbon atom is substituted with an oxo moiety (=O). The alkoxy moiety is an -O-alkyl moiety. In this context, haloalkyl should be construed as alkyl substituted with halogen. Preferred haloalkyls are fluorinated alkyls, more preferably perfluorinated alkyls, and most preferably trifluoromethyl. In the context of the present invention, halogen is fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferred halogens are fluorine, chlorine and bromine, more preferred halogens are fluorine or chlorine, and most preferred halogen is fluorine.

[0053] In the context of the present invention, the number of carbon atoms in moieties such as alkyl, acyl, cycloalkyl, heterocycloalkyl, etc. is indicated, for example, as C1-4, and this non-limiting example indicates that 1 to 4 carbon atoms, for example 1, 2, 3 or 4 carbon atoms, are contemplated. Similarly, C2-4 alkyl has 2, 3 or 4 carbon atoms. The number of carbon atoms can be represented as the total number of carbon atoms without counting further substitutions, the total number of carbon atoms, or the number of carbon atoms found in the longest continuous internal sequence of carbon atoms. Preferably, the number of carbon atoms is represented as the total number of carbon atoms without counting further substitutions.

[0054] In the context of the present invention, an unsubstituted alkyl group has the general formula C n H 2n+1and may be straight-chain or branched-chain. The unsubstituted alkyl group may also contain a cyclic moiety, and thus may have the accompanying general formula C n H 2n-1 and may have. Optionally, the alkyl group is substituted with one or more substituents further specified herein. Examples of suitable alkyl groups include, but are not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, etc. Preferred alkyl groups are straight-chain or branched-chain, most preferably straight-chain. A cycloalkyl group is a cyclic alkyl group, and preferred cycloalkyl groups are cyclopropyl and cyclobutyl. A heterocycloalkyl group is a cycloalkyl group in which at least one CH2 moiety is replaced by a heteroatom. Preferred heteroatoms are S, O, and N. Preferred C 1~4 alkyl groups are -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, cyclopropyl, and cyclobutyl, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, and -C(CH3)3.

[0055] The alkyl groups of the present invention are optionally unsaturated. In a preferred embodiment, the alkyl is not unsaturated. The unsaturated alkyl group is preferably an alkenyl group or an alkynyl group. In the context of the present invention, an unsubstituted alkenyl group has the general formula C n H 2n-1 and may be straight-chain or branched-chain. Examples of suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, pentenyl, etc. The unsubstituted alkenyl group may also contain a cyclic moiety, and thus may have the accompanying general formula C n H 2n-3It may have. Preferred alkenyl groups are linear or branched, most preferably linear. A very preferred unsaturated cycloalkyl group is an aryl group such as phenyl.

[0056] An unsubstituted alkynyl group has the general formula C n H 2n-3 and may be linear or branched. The unsubstituted alkynyl group may also contain a cyclic moiety and thus may have the accompanying general formula C n H 2n-5 Optionally, the alkynyl group is substituted with one or more substituents further specified herein. Examples of suitable alkynyl groups include, but are not limited to, ethynyl, propargyl, n-but-2-ynyl, n-but-3-ynyl, and octynes such as cyclooctyne. Preferred alkyl groups are linear or branched, most preferably linear.

[0057] An aryl group is aromatic and generally contains at least 6 carbon atoms and may include monocyclic, bicyclic, and polycyclic structures. Optionally, the aryl group is substituted with one or more substituents further specified herein. Examples of aryl groups include groups such as phenyl, naphthyl, anthracyl. A heteroaryl group is aromatic and contains 1 to 4 heteroatoms selected from the group consisting of S, O, and N. Due to the heteroatoms, the ring size can be less than 6.

[0058] In the present invention, in each case, alkyl, acyl, cycloalkyl, and heterocycloalkyl are preferably optionally substituted with one or more moieties selected from halogen, oxy, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, and trifluoromethyl, and in each case, a heteroatom such as N, O, or S may be inserted, and alkyl, acyl, alkoxyl, cyclil, and heterocyclyl are optionally unsaturated in each case. The insertion by a heteroatom means the insertion by one or more heteroatoms. In this regard, preferably 20 or less, more preferably 1, 2, 3, 4, or 5 heteroatoms are inserted, even more preferably 1, 2, or 3, preferably 1 or 2, and most preferably 1 heteroatom is inserted. Preferably, all inserted heteroatoms are of the same element. As a non-limiting example, C5 alkyl -CH2-CH2-CH2-CH2-CH3 when a heteroatom is inserted can be -CH2-CH2-O-CH2-CH2-O-CH3. In a preferred embodiment, there is no optional substitution. In a preferred embodiment, both substitution and unsaturation are present.

[0059] In a preferred embodiment, when C1 - 4 alkyl is optionally unsaturated and optionally substituted, it can be C1 - 4 alkyl, C1 - 4 acyl, C2 - 4 alkenyl, C2 - 4 alkynyl, C3 - 4 cycloalkyl, C3 - 4 heterocycloalkyl optionally substituted with one or more moieties selected from halogen, oxy, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, and trifluoromethyl. In a preferred embodiment, when C1 - 4 alkyl is optionally unsaturated and optionally substituted, it can be C1 - 4 alkyl, C1 - 4 acyl, C2 - 4 alkenyl, C2 - 4 alkynyl, C3 - 4 cycloalkyl, or C3 - 4 heterocycloalkyl optionally substituted with one or more moieties selected from halogen, oxy, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, and trifluoromethyl.

[0060] -C(=O)-oligopeptides can include any oligopeptides, but are preferably short, such as containing only 4, 3, 2, or 1 amino acid. The -C(=O) moiety of the -C(=O)-oligopeptide can be the C-terminus of the oligopeptide, but can also be an additional carbonyl moiety included in an amide bond with the N-terminus of the oligopeptide. The latter is preferred. The oligopeptide may have a free end, but is preferably amidated. Preferred oligopeptides for the -C(=O)-oligopeptide include up to 3 amino acids selected from alanine and glycine, more preferably glycine, even more preferably 1 or 2 amino acids, most preferably 1 amino acid, such as glycine. A highly preferred -C(=O)-oligopeptide is -C(=O)-NH-CH2-C(=O)-NH2.

[0061] The amino acid side chain can be any amino acid side chain known in the art. Preferably, in each case, independently, it is H, or optionally substituted, optionally unsaturated C2-6(halo)alkyl-NH2, C1-6(halo)alkyl, 5-10 membered (hetero)aryl, C1-4(halo)alkyl-[5-10 membered (hetero)aryl], C2-6(halo)alkyl-N(H)C(NH2)(=NH), C1-6(halo)alkyl-C(O)-NH2, or C1-4(halo)alkyl-[3-10 membered (hetero)cycloalkyl]. In some embodiments, the amino acid side chain is not optionally substituted and is not optionally unsaturated. In some embodiments, the amino acid side chain is optionally substituted and is not optionally unsaturated. In some embodiments, the amino acid side chain is not optionally substituted and is optionally unsaturated. Particularly preferred optional substitutions are halogen, C1-3(halo)alkyl, or C1-3(halo)alkoxyl, more preferably halogen, -CH3 and -O-CH3. Here, any substitution within the amino acid side chain is preferably -OH, -SH, -SeH, -S-CH3, -O-CH3, and -COOH, more preferably -OH, -SH, and -S-CH3, most preferably -OH. The amino acid side chain is preferably H, C2-5(halo)alkyl-NH2, C1-4(halo)alkyl, 5-9 membered (hetero)aryl, C1-2(halo)alkyl-[5-9 membered (hetero)aryl], C2-4(halo)alkyl-N(H)C(NH2)(=NH), C1-4(halo)alkyl-C(O)-NH2, or C1-2(halo)alkyl-[3-9 membered (hetero)cycloalkyl]. Here, C2-6(halo)alkyl-NH2 is preferably -CH2-CH2-CH2-NH2 or -CH2-CH2-CH2-CH2-NH2. Here, 5-10 membered (hetero)aryl is preferably phenyl. Here, optionally substituted C1-4(halo)alkyl-[5-10 membered (hetero)aryl] is preferably -CH2-phenyl, -CH2-CH2-phenyl, -CH2-imidazolyl, -CH2-CH2-imidazolyl, -CH2-indolyl, -CH2-CH2-indolyl, -CH2-hydroxyphenyl, -CH2-CH2-hydroxyphenyl. Here,Optionally substituted C1-6 (halo) alkyl is preferably -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-OH, -CH2-SH, -CH2-SeH, -CH2-CH2-CH2-S-CH3, -CH(CH3)-CH2-OH, -CH2-CH2-COOH, or -CH2-COOH, more preferably -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)CH2-CH3, -CH2-OH, -CH2-SH, -CH2-SeH, -CH2-CH2-CH2-S-CH3, or -CH2(CH3)-CH2-OH, where C2-6 (halo) alkyl-N(H)C(NH2)(=NH) is preferably -CH2-CH2-CH2-N-C(=NH)-NH2, and where C1-6 (halo) alkyl-C(O)-NH2 is preferably -CH2-CH2-C(O)NH2 or -CH2-C(O)NH2.,

[0062] The targeting moiety can be any moiety known to target or bind to a target of interest. Examples of targeting moieties are cell-penetrating peptides, receptor ligands, and antibodies or fragments thereof. The compounds according to the invention are also targeting moieties since they bind to the spike protein. This means that the compound of general formula (I) can be a dimer linked via a linker. The targeting moiety is preferably linked via a linker to the remainder of the linker, and this linker preferably contains one or more amino acids, oligo(ethylene glycol) or C2-12 hydrocarbons. Preferred targeting moieties are dimerizing linkers. Further features of the dimerizing linker are shown below. Thus, the dimer so formed contains two macrocycles. Preferably, the peptide and X are the same for both macrocycles. Preferably, the linker is the same for both macrocycles.

[0063] In a preferred embodiment, the linker has the general formula (L1):

Chemical formula

[0064] Preferably, the linker has the general formula (L2):

Chemical formula

[0065] In some embodiments, the linker has the general formula (L3):

Chemical formula

[0066] Preferred examples of the linker are those having a general formula selected from (L4a) to (L4h).

[0067]

Table 2

[0068] (L4a) to (L4g) are more preferred, (L4a) and (L4b) are even more preferred, and (L4a) is most preferred. In a preferred embodiment, when present, the chirality of the above moiety is as shown for the moiety contained in dimer 1.

[0069] The dimerizing linker otherwise links two individual compounds of general formula (I) and results in a compound containing two macrocycles. The nature of the dimerizing linker is not critical as long as it links the two macrocycles to each other. Those skilled in the art know how to select a dimerizing linker and can form dimers from the individual macrocycles described herein. The general formula of the dimer is general formula (dimer 1):

Chemical formula

[0070] For ease of expression, when the dimerizing linker is represented schematically, it is generally represented as a mere shape containing the words "dimerizing linker" herein, where the dimerizing linker represents both the linker and the second macrocycle as shown in (dimer 1). Examples of linkers suitable for use in the compounds of general formula (dimer 1) are shown below. In a preferred embodiment, when present, the chirality of the following moiety is as shown for the moiety contained in dimer 1. Among the following, DiL4 is most preferred.

[0071]

Table 3

[0072] The dimerizing linker itself that connects the two macrocycles can be selected by those skilled in the art. It preferably has a backbone length of 6 to 120 atoms, is optionally substituted, more preferably 10 to 80 atoms, even more preferably 15 to 70 atoms, even more preferably 20 to 60 atoms, even more preferably 30 to 55 atoms, more preferably 40 to 55 atoms, most preferably 45 to 54 atoms, for example, having a backbone length of 50, 51 or 52 atoms, and 51 atoms are particularly preferred among them. For the convenience of their synthesis, the atoms are preferably short oligoethylene glycol repeats or short alkyl chains connected via optionally amide, urea or carbamate bonds. Any substitution is generally for facilitating synthesis, preferably =O, halogen, C1-4 hydrocarbon, C1-4 acyl, C1-4 alkoxy, -C(=O)-oligopeptide, -SH, -S-(C1-4 hydrocarbon), -NH2, -NH-(C1-4 hydrocarbon), -NH-(C1-4 acyl), -N-(C1-4 hydrocarbon)2, -N-(C1-4 acyl)2, or amino acid side chains, all of which are as described above, more preferably, they are =O, -C(=O)-oligopeptide, or amino acid side chains, most preferably -C(=O)-oligopeptide, for example -C(=O)-NH-CH2-C(=O)-NH2. Preferred dimerizing linkers are as follows.

[0073]

Table 4

[0074] In some embodiments, it is DL1, DL2, or DL3. In some embodiments, it is DL1, DL4-DL9. In some embodiments, it is DL1 or DL4. In some embodiments, it is DL1, DL5, DL6, or DL8. DL5 is highly preferred. A preferred compound according to the present invention includes a linker that is DiL4 and the dimerizing linker is DL5. A compound in which the peptide contains SEQ ID NO: 1 is preferred. Such dimers are preferred, and such embodiments are dimer 1: [Chemical formula] It is represented by

[0075] [Further definition of the compound] In a preferred embodiment, the peptide has 15 amino acid residues and / or the peptide contains a sequence represented by any one of SEQ ID NOs: 1 to 2 and / or the linker has any one of general formulas (L4a) to (L4h) and / or X is NH.

[0076] Preferably, the peptide has 15 amino acid residues, and the peptide contains a sequence represented by any one of SEQ ID NOs: 1 to 2. Preferably, the peptide has 15 amino acid residues, the peptide contains a sequence represented by any one of SEQ ID NOs: 1 to 2, and X is NH. Preferably, the peptide has 15 amino acid residues, the peptide contains a sequence represented by any one of SEQ ID NOs: 1 to 2, and the linker has any one of general formulas (L4a) to (L4h). Preferably, the peptide has 15 amino acid residues, the peptide contains a sequence represented by any one of SEQ ID NOs: 1 to 2, the linker has any one of general formulas (L4a) to (L4h), and X is NH.

[0077] In a preferred embodiment, the compound of general formula (I) is cyclic peptide 1 or a salt thereof. [Chemical formula]

[0078] A preferred cyclic peptide 1 is cyclic peptide 1L. [Chemical formula]

[0079] In a preferred embodiment, the compound of general formula (I) is cyclic peptide 2 or a salt thereof. [Chemical formula]

[0080] The preferred cyclic peptide 2 is cyclic peptide 2L. [Chemical formula]

[0081] [Composition] The present invention provides a composition comprising at least one compound of general formula I and a pharmaceutically acceptable excipient, preferably for use according to the present invention (the use is described elsewhere in this specification). Such a composition is referred to herein as a composition according to the present invention. A preferred composition according to the present invention is a pharmaceutical composition. In a preferred embodiment, the composition according to the present invention is formulated for oral, sublingual, parenteral, intravascular, intravenous, subcutaneous, or transdermal administration, optionally by inhalation, preferably for oral administration. Further features and definitions of the administration methods are shown in the section on formulations and administration.

[0082] [Formulations and Administration] The composition containing the above compound can be prepared as a pharmaceutical formulation or as various other vehicles such as foods for humans or animals, such as medical foods and dietary supplements. The compound and the composition can be formulated with other physiologically acceptable materials that can be ingested, such as, but not limited to, foods. Additionally, or alternatively, the compositions described herein may be administered orally in combination with (separate) administration of food.

[0083] The composition or compound according to the present invention can be administered alone or in combination with other pharmaceuticals and can be combined with its physiologically acceptable carrier. In particular, the compounds described herein can be formulated as pharmaceutical compositions by formulations containing pharmaceutically or physiologically acceptable excipient carriers and additives such as vehicles. Suitable pharmaceutically or physiologically acceptable excipients, carriers and vehicles include processing agents and drug delivery regulators and promoters, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl - P - cyclodextrin, polyvinylpyrrolidone, low melting point wax, etc., and any combination of two or more thereof. Other suitable pharmaceutically acceptable excipients are incorporated herein by reference, "Remington’s Pharmaceutical Sciences," Mack Pub.Co., New Jersey (1991), and "Remington: The Science and Practice of Pharmacy," Lippincott Williams & Wilkins, Philadelphia, 20th Edition (2003), 21st Edition (2005) and 22nd Edition (2012).

[0084] The compositions for use according to the present invention can be manufactured by conventional mixing, dissolving, granulating, tablet - coating, levigating, emulsifying, encapsulating, entrapping or lyophilization processes that can result in, for example, liposome formulations, coacervates, oil - in - water emulsions, nanoparticle / microparticle powders, or any other shape or form well - known in the art. Thus, the compositions for use according to the present invention can be formulated by conventional methods using one or more physiologically acceptable carriers including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically useful preparation. Suitable formulations depend on the route of administration selected.

[0085] For injection, the compounds and compositions for use according to the invention can be formulated by being placed in an aqueous solution, preferably in a physiologically compatible buffer, such as Hank's solution, Ringer's solution or saline buffer. In the case of transmucosal administration, penetrants appropriate for the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art.

[0086] Oral and parenteral administrations can be used when the compounds and compositions for use are formulated by combining them with pharmaceutically acceptable carriers well-known in the art or by using them as food additives. Such strategies enable the compounds and compositions for use according to the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the subject to be treated. Preparations or pharmaceutical preparations for oral use can be prepared by using solid excipients, optionally grinding the obtained mixture after adding appropriate adjuvants if necessary to obtain a tablet or dragee core, and processing the obtained mixture of granules. Suitable excipients are, in particular, fillers such as sugars like lactose, sucrose, mannitol or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinyl pyrrolidone (PVP), etc. If desired, disintegrants such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or its salts such as sodium alginate can be added. Furthermore, co-formulations can be prepared using absorption enhancers known in the art.

[0087] Compounds and compositions that can be administered orally include push-fit capsules made of gelatin, as well as soft-sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be added. All formulations for oral administration must be in a dosage suitable for such administration.

[0088] For buccal administration, the compounds and compositions for use according to the present invention can be administered in the form of tablets or lozenges formulated by conventional methods.

[0089] The compounds and compositions for use according to the present invention can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. In this way, it is also possible to target specific organs, tissues, tumor sites, inflammatory sites, etc. Formulations for infectious diseases can be provided in unit dosage forms, such as ampoules, or in multiple-dose containers, with the addition of preservatives. The present composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. This formulation is preferred because it enables specific targeting of muscle tissue.

[0090] Compositions for parenteral administration include aqueous solutions of the composition in water-soluble form. Additionally, suspensions can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that enhance the solubility of the composition to enable the preparation of a high-concentration solution.

[0091] Alternatively, one or more components of the composition may be in powder form for constitution with a suitable vehicle, such as sterile water free of pyrogens, before use.

[0092] The compositions for use according to the present invention may also include a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0093] The compositions for use according to the present invention include compounds and compositions containing the active ingredient in an amount effective to achieve their intended purposes. More specifically, a therapeutically effective amount means an amount of a compound effective for preventing, stabilizing, alleviating, reversing or remitting the cause or symptoms of a disease, or for prolonging the survival, mobility or independence of a subject being treated. Determination of a therapeutically effective amount is within the ability of one of ordinary skill in the art, especially in light of the disclosure provided herein. For any compound and composition used in the present invention, a therapeutically effective amount or dosage can first be estimated from cell culture assays, as exemplified herein. The dosage can vary within this range depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see, for example, Fingl, et al., 1975, “The Pharmacological Basis of Therapeutics” Ch. 1 p. 1). The amount of the compound and composition administered will, of course, depend on the subject being treated, the weight of the subject, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0094] An "effective amount" of a compound or composition is an amount sufficient to reduce or eliminate one or more symptoms of a disease, or retard the progression of one or more symptoms of a disease, or reduce the severity of one or more symptoms of a disease, or suppress the symptoms of a disease, or suppress the symptoms of a deleterious symptom of a disease when administered to a subject. The effective amount can be given in one or more administrations.

[0095] The "effective amount" can, in combination with carrier materials, produce a single dosage form that varies depending on the host to which the active ingredient is administered and the particular mode of administration. The selected unit dosage is usually prepared and administered so as to provide the desired final concentration of the compound in the blood.

[0096] Preferably, the effective amount for an adult (i.e., the total effective daily dose) is defined herein as a total daily dose of about 0.01 - 2000 mg, or about 0.01 - 1000 mg, or about 0.01 - 500 mg, or about 5 - 1000 mg, or about 20 - 800 mg, or about 30 - 800 mg, or about 30 - 700 mg, or about 20 - 700 mg, or about 20 - 600 mg, or about 30 - 600 mg, or about 30 - 500 mg, about 30 - 450 mg, or about 30 - 400 mg, or about 30 - 350 mg, or about 30 - 300 mg, or about 50 - 600 mg, or about 50 - 500 mg, or about 50 - 450 mg, or about 50 - 400 mg, or about 50 - 300 mg, or about 50 - 250 mg, or about 100 - 250 mg, or about 150 - 250 mg. In the most preferred embodiment, the effective amount is about 200 mg. In a preferred embodiment, the present invention provides a compound for use according to the present invention or a composition for use according to the present invention, which is characterized in that it is administered to a subject in an amount in the range of 0.1 - 1500 mg / day, preferably 0.1 - 1000 mg / day, more preferably 0.1 - 400 mg / day, even more preferably 0.25 - 150 mg / day, for example about 100 mg / day.

[0097] Alternatively, the effective amount of the compound is preferably administered per kg of body weight, preferably in the case of an adult. Thus, preferably in the case of an adult, the total daily dose is from about 0.05 to about 40 mg / kg, from about 0.1 to about 20 mg / kg, from about 0.2 mg / kg to about 15 mg / kg, or from about 0.3 mg / kg to about 15 mg / kg, or from about 0.4 mg / kg to about 15 mg / kg, or from about 0.5 mg / kg to about 14 mg / kg, or from about 0.3 mg / kg to about 14 mg / kg, or from about 0.3 mg / kg to about 13 mg / kg, or from about 0.5 mg / kg to about 13 mg / kg, or from about 0.5 mg / kg to about 11 mg / kg.

[0098] Alternative dosages that may be used are effective amounts of the compounds for use according to the invention within the dosage ranges of from about 0.1 μg / kg to about 300 mg / kg, or within the range of from about 1.0 μg / kg to about 40 mg / kg body weight, or within the range of from about 1.0 μg / kg to about 20 mg / kg body weight, or within the range of from about 1.0 μg / kg to about 10 mg / kg body weight, or within the range of from about 10.0 μg / kg to about 10 mg / kg body weight, or within the range of from about 100 μg / kg to about 10 mg / kg body weight, or within the range of from about 1.0 mg / kg to about 10 mg / kg body weight, or within the range of from about 10 mg / kg to about 100 mg / kg body weight, or within the range of from about 50 mg / kg to about 150 mg / kg body weight, or within the range of from about 100 mg / kg to about 200 mg / kg body weight, or within the range of from about 150 mg / kg to about 250 mg / kg body weight, or within the range of from about 200 mg / kg to about 300 mg / kg body weight, or within the range of from about 250 mg / kg to about 300 mg / kg body weight. Other dosages that may be used are about 0.01 mg / kg body weight, about 0.1 mg / kg body weight, about 1 mg / kg body weight, about 10 mg / kg body weight, about 20 mg / kg body weight, about 30 mg / kg body weight, about 40 mg / kg body weight, about 50 mg / kg body weight, about 75 mg / kg body weight, about 100 mg / kg body weight, about 125 mg / kg body weight, about 150 mg / kg body weight, about 175 mg / kg body weight, about 200 mg / kg body weight, about 225 mg / kg body weight, about 250 mg / kg body weight, about 275 mg / kg body weight, or about 300 mg / kg body weight.

[0099] In a preferred embodiment of the present invention, the "subject", "individual" or "patient" is understood to be an individual organism, preferably a vertebrate, more preferably a mammal, even more preferably a primate, and most preferably a human.

[0100] [Use] The present invention provides a compound according to the present invention or a composition according to the present invention for use as a medicament. This medicament may be for treating, preventing or alleviating coronavirus infection. The viral infection is preferably an infection by a respiratory virus such as RSV, pneumovirus, influenza virus or coronavirus. More preferably, the viral infection is an infection by a coronavirus, for example, SARS-CoV or SARS-CoV-1, MERS-CoV or SARS-CoV-2. Most preferably, the viral infection is an infection by SARS-CoV-2, that is, COVID-19. The administration method has been described above.

[0101] A preferred coronavirus infection is SARS-CoV-2 infection. Preferably, the medicament is for treating a viral infection, preferably a coronavirus infection, more preferably a SARS-CoV-2 infection. The treatment is preferably prophylactic treatment. Inhibition of viral spike protein binding reduces viral infectivity and ensures effective prophylactic treatment. In some embodiments, the medicament is for treating, alleviating or preventing COVID-19.

[0102] Also provided is the use of either a compound of general formula I or a composition according to the present invention for the treatment, prevention or alleviation of a viral infection in a subject in need thereof, the use comprising administration of an effective amount of the compound of general formula I or the composition according to the present invention to the subject.

[0103] [Method] The present invention provides a method for modulating the conformational dynamics of a viral spike protein, in vitro, in vivo, or ex vivo, the method comprising contacting the viral spike protein with a compound according to the present invention or a composition according to the present invention. In some embodiments, the method is in vitro or ex vivo. In some embodiments, the method is in vitro.

[0104] Preferably, the method is for modulating the conformational dynamics of the viral spike protein of a coronavirus particle, more preferably an SARS-CoV-2 particle. Preferably, this modulation inhibits the interaction between the spike protein and the ACE2 receptor. In some embodiments, this modulation is for inhibiting the opening of the spike RBD. Preferably, this modulation is for stabilizing the closed conformation of the spike RBD, more preferably the SARS-CoV-2 spike protein RBD.

[0105] The method preferably includes uses as previously defined herein. The viral spike protein can be present inside the cell, in the cell culture medium, or in a sample or subject. The viral spike protein is preferably contained in viral particles. Preferred methods include contacting a cell, sample, or subject with a compound or composition of general formula I as previously defined herein. In the context of the present invention, contacting a cell, sample, or subject with a compound or composition of general formula I can include adding such a compound or composition of general formula I to the medium in which the cells are cultured. Contacting a cell with a compound or composition of general formula I can also include adding such a compound or composition of general formula I to a medium, buffer, or solution in which the cells are suspended, cover the cells, or the sample is mixed. Further methods of administration are defined elsewhere herein. The cells can be cells from a sample obtained from a subject. Such a sample can be a sample previously obtained from the subject. In an embodiment of this aspect, the sample may be previously obtained from a human subject. In an embodiment of this aspect, the sample may be obtained from a non-human subject. In a preferred embodiment of this aspect, obtaining the sample is not part of the method according to the present invention.

[0106] The present invention also provides a method for treating a viral infection, the method comprising administering to a subject a compound according to the present invention or a composition according to the present invention. Further features and definitions are as indicated elsewhere herein.

[0107] [General Definitions] When the structural formula or chemical name is understood by those skilled in the art to have a chiral center, but chirality is not indicated, for each chiral center, all three of the racemic mixture, the pure R enantiomer, and the pure S enantiomer are individually mentioned. Whenever a fragment of a molecule, often referred to as a moiety, is represented, a dotted line or a wavy line indicates which bond connects it to the whole molecule, or an asterisk (*) indicates that the represented moiety is connected to the rest of the molecule. This asterisk does not mean an atom, and the bond where the dotted line or wavy line intersects does not convey information about which atom is on the non - moiety side of the bond.

[0108] Whenever a parameter of a substance is discussed in the context of the present invention, unless otherwise specified, the parameter is assumed to be determined, measured, or specified under physiological conditions. Physiological conditions are known to those skilled in the art and include an aqueous solvent system, atmospheric pressure, a pH value of 6 - 8, a temperature in the range of room temperature to about 37 °C (about 20 °C to about 40 °C), and appropriate concentrations of buffer salts or other components. Charge is often understood to be related to equilibrium. A moiety said to carry or bear a charge is one in which the state of carrying or bearing such a charge is more frequently found than the state of not carrying or bearing such a charge. Thus, as understood by those skilled in the art, an atom shown to be charged in the present disclosure may be uncharged under certain conditions, and a neutral moiety may be charged under certain conditions.

[0109] In the context of the present invention, a decrease or increase in a parameter being evaluated means a change of at least 5% of the value corresponding to that parameter. More preferably, the decrease or increase in the value means a change of at least 10%, even more preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 90%, or 100%. In the latter case, the detectable value associated with the parameter may no longer exist.

[0110] The use of a substance as a medicament described herein can also be construed as the use of the substance in the manufacture of a medicament. Similarly, whenever a substance is used as a medicament, it can also be used for the manufacture of a medicament or in a method. In a preferred embodiment, the compounds and compositions according to the invention are for use in the methods according to the invention or for the uses according to the invention.

[0111] In this specification and the claims thereof, the verb "comprise" and its inflected forms are used in its non-limiting sense, meaning that the items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that there may be more than one of that element, unless the context clearly requires that there be only one of the elements. Thus, the indefinite article "a" or "an" usually means "at least one". The term "about" or "approximately", when used in connection with a numerical value (e.g., about 10), means that the value can be plus or minus 5% of a given value (10), preferably plus or minus 1% of that value.

[0112] All patent and literature references cited herein are hereby incorporated by reference in their entirety.

Examples

[0113] [1. Preparation of Compounds] The peptide was synthesized using microwave-assisted Fmoc solid-phase peptide synthesis on Rapp Polymere (Germany) tentagel S RAM resin with a Liberty Blue (CEM) peptide synthesizer. Each coupling step of 4 minutes was carried out at 90 °C in DMF using 5 equivalents of amino acid, 5 equivalents of Oxyma Pure and 10 equivalents of N,N'-diisopropylcarbodiimide (DIC). Histidine coupling was carried out instead at 50 °C for 10 minutes. Fmoc deprotection was carried out at 90 °C for 1 minute using 20% piperidine in DMF. After automated synthesis, N-terminal chloroacetylation by using 5 equivalents of chloroacetic acid instead of amino acid in the described coupling step, or N-acetylation by treatment with 20% acetic anhydride in DMF at 65 °C for 2 minutes was carried out. Peptide cleavage, overall deprotection, cyclization and subsequent purification were carried out by adding cleavage solution (90% trifluoroacetic acid, 5% water, 2.5% triisopropylsilane, 2.5% 1,2-ethanedithiol) and incubating for 2 - 3 hours with gentle shaking. The resin was filtered off and the cleaved and deprotected peptide was precipitated by adding to 10-fold excess of cold diethyl ether. The peptide was pelleted by centrifugation at 5,000 rcf for 5 minutes and the supernatant was removed. Further diethyl ether was added, the pellet was resuspended and centrifuged again, and the supernatant was removed. The pellet was washed in this way for a total of 3 times and then dried in air and dissolved in dimethyl sulfoxide to approximately 5 mM. Then, a few drops of DIPEA base were added and the cyclization reaction was allowed to proceed overnight and then quenched with an equal volume of trifluoroacetic acid. The resulting solution was directly loaded onto a C18 column for HPLC purification using a 10 - 70% acetonitrile gradient in water. The purified peptide was characterized by HPLC for purity and coupled to mass spectrometry for identification.

[0114] [2. Characterization of the compound] [2.1 Physical characterization] For the provided compounds, both the calculated and measured mass spectrometry data are shown below (for cyclic peptide 1L, excluding S1b3inL1lin and SARS2L1lin where the linker is L4a, X is NH, and Ac-[sequence of SEQ ID NO]-NH2). The peptides were sufficiently pure as determined by HPLC analysis.

[0115] [Table 5]

[0116] [2.2 Binding to Spike Protein] Compounds that bind to the spike protein of SARS-CoV-2 virions were identified by mRNA display of the compounds using affinity panning with immobilized spike protein followed by library regeneration through eight consecutive rounds of affinity enrichment as described in van Haren et al., RSC Chem. Biol. 2, 1546 - 1555, 2021. Further panning of the enriched library obtained from the third round of the above selection was performed twice using the isolated S1b domain of the spike protein. All enriched libraries were subjected to high-throughput sequencing, and the sequences of the binding compounds were determined by analysis of highly enriched unique sequences. The enrichment levels of the selected compounds are summarized in the following table and were enriched from an estimated starting fraction of 1 in 10 12 sequences (0.0000000001%).

[0117] [Table 6]

[0118] The binding of a subset of these identified compounds to the spike protein was further evaluated by a thermal shift assay, and the magnitudes of the protein melting point changes were summarized in the following table. In this assay, purified compounds were prepared as 400 μM stock solutions in DMSO based on UV absorbance at 280 nm using the calculated extinction coefficient (Expasy ProtParam, Swiss Bioinformatics Resource Portal). The thermal shift assay reaction mixture for measurements using full-length SARS-CoV-2 spike contained 10 μM compound, 0.25 mg / ml protein, and 5× SYPRO Orange dye (Thermo Fisher Scientific) in Dulbecco's phosphate-buffered saline (Gibco). The data collected for the S1b3inL1 compound had varying concentrations of 0.1 mg / ml full-length SARS-CoV-2 spike. An equal volume of DMSO was added for the control experiment compared to the compound solution to obtain a final concentration of 5% DMSO. The assay was performed on a Bio-Rad CFX96 PCR instrument in 0.5 °C incremental steps from 20 °C to 75 °C for 10 seconds using the "Melting Assay" protocol (FRET filter settings). All measurements were performed in duplicate and averaged. The melting temperature (Tm) was determined using the temperature corresponding to the highest value of the d(RFU) / dT peak.

[0119] [Table 7]

[0120] [2.3 Protective Binding] Among the above compounds found to bind to the spike protein, some were observed to confer a protective effect in a cell assay of SARS2-S pseudotyped VSV infection (Wang et al., Nat.Comm. 11, 2251, 2020), and subsequently, a subset of these compounds was tested against the full SARS-CoV-2 virus using the R-20 platform (Aggarwal et al., Nat.Mol.Biol. 7, 896 - 908, 2022). This test is summarized in the following table.

[0121]

Table 8

[0122] Among these inhibitory compounds, the most promising compound containing SEQ ID NO: 1 was further shown to be protective in a cell assay involving SARS2-S pseudotyped VSV infection derived from various mutants of interest. This shows a very broad range of activity against spike-binding molecules. The maximum half-inhibitor effect (IC 50 ) of this compound in these assays is summarized in the following table.

[0123]

Table 9

[0124] This compound was further shown to be protective in a cell assay of infection with VSV pseudotyped with spike proteins from several different sarbecoviruses. This indicates that the binding site and mechanism of action are highly conserved. The maximum half-inhibitor effect (IC 50 ) of this compound in these assays is summarized in the following table.

[0125]

Table 10

[0126] [2.4 Dimerization further increases potency] As described for the other compounds above, dimer compounds were synthesized, using a lysine residue as the branching point at the initial stage of the synthesis. This was carried out using the component N,N'-bis-Fmoc-L-lysine, in which case both the backbone and the side-chain amine groups can be liberated by treatment with piperidine during the standard deprotection cycle. Subsequently, both arms of the dimer were extended with the same reaction in each reaction cycle. The reagent equivalents were calculated based on the dimer compound, meaning that the equivalents were doubled for the amino acids incorporated prior to this branching. Compounds with different dimerization linkers were produced (the peptide is SEQ ID NO: 1, the linker is DiL4, X is NH, see Table S2.4). Characterization of the resulting dimer compounds by mass spectrometry is shown in the following table. HPLC analysis revealed that all the compounds were sufficiently pure.

[0127]

Table 11

[0128] The resulting dimeric macrocyclic compounds were tested for inhibition of SARS-CoV-2 infection using pseudovirus in a cell assay, and the activities were summarized in the following table.

[0129]

Table 12

[0130] These data indicate that dimerization leads to an increase in activity, and this increased activity is not strongly dependent on the linker used.

[0131] [3. Robustness of this compound] Within the compound where the linker is L4a and X is NH (for cyclic peptide 1L), each amino acid position of the peptide of SEQ ID NO: 1 was systematically substituted with alanine. The inhibitory effect on infection was measured in a pseudovirus cell infection assay for the resulting compounds, and the data were summarized in the following table. In this table, "n.i." indicates that no inhibition was observed.

[0132]

Table 13

[0133] For many of the compounds in the above table, some degree of activity was retained, and the degree of this activity was used as an indicator of the importance of the original residue at that position. Compounds containing peptides with mutations at positions 1, 7, and 12 showed no inhibition, so these positions are particularly relevant to the activity. Peptides with mutations at positions 2, 3, 8, 10, 11, and 13, and to some extent at position 9, showed attenuated inhibition, so these positions are thought to contribute to the activity. Peptides with mutations at positions 4, 5, and 6 showed some loss of inhibition, so these positions are thought to contribute to the activity to some extent. Peptides with mutations at positions 14 and 15 showed only a slight loss of inhibition, so these positions are not considered important for the activity. These results demonstrate that the compounds according to the present invention are resistant to peptide changes without losing their activity.

[0134] Next, the positions were replaced with amino acids other than alanine, and more mutants were assayed. The double mutations were highly tolerant. For the single mutations, the results are shown in Table S4, where the one-letter amino acid code is used (along with X and Z defined previously herein), and the top line indicates the positions in SEQ ID NO: 1 from the N-terminus to the C-terminus. The columns with mutations indicate at which positions the mutations were made. Table S4 shows the binding affinities normalized to the binding affinity of SEQ ID NO: 1 representing 100% binding. Results indicated as "-" represent a decrease in binding. Results indicated as "0" represent substantially similar binding. Results indicated as "1" represent the original sequence. Results indicated as "+" represent binding of about 105 - 200%. Results indicated as "++" represent binding of about 200 - 300%. Results indicated as "+++" represent binding of about 300 - 500%. Results indicated as "++++" represent binding of greater than about 500%.

[0135]

Table 14

Claims

1. General formula (I): 【Chemistry 1】 A compound of, During the ceremony, The peptide is an oligopeptide having 13 to 17 amino acid residues, preferably comprising the oligopeptide represented by Sequence ID No. 1 having up to 5 amino acid substitutions. The linker is a linking portion that, together with X, connects the N-terminus and C-terminus of the peptide to form a macrocyclic structure. X is a compound that is either O or NH. Or a salt of such a compound.

2. The peptide is an oligopeptide having 13 to 17 amino acid residues. The first amino acid is arginine, lysine, histidine, leucine, isoleucine, or valine. The seventh amino acid is isoleucine, leucine, or valine. The twelfth amino acid is isoleucine, leucine, or valine. The compound according to claim 1.

3. The compound according to claim 1, wherein the peptide is an oligopeptide represented by Sequence ID No. 1, having a length of 15 to 17 amino acids, preferably 15 amino acids, and having 5, 4, 3, 2, or 1 amino acid substitutions.

4. Within the peptide, If the 1st position is substituted with another amino acid, it is preferably Z, Q, L, or C, more preferably Q, K, or C, and most preferably K. If the 2nd position is substituted with another amino acid, it is preferably Z or C, more preferably C. If the 3rd position is substituted with another amino acid, it is preferably A, L, Z, X, S, T, N, Q, H, L, R, or C, more preferably L, S, T, N, K, R, or C, and most preferably C. If the 4th position is substituted with another amino acid, it is preferably A, Z, P, or C, more preferably Z, P. Or C, most preferably substituted with C, if the 5th position is substituted with another amino acid, it is preferably A, F, Y, X, W, S, N, H, R, D or C, more preferably A, Y, X, W, S, N, H or C, most preferably X, W or C, if the 6th position is substituted with another amino acid, it is preferably A, I, Y, X, W, S, T, H, D, E or C, more preferably X, W, E or C, most preferably C, if the 7th position is substituted with another amino acid, it is substituted with V, the 8th position is unsubstituted, and the 9th position is substituted with another amino acid. In combination, it is preferably substituted with F, Z, or W, more preferably with Z or W, most preferably with Z, and if the 10th position is substituted with another amino acid, it is preferably substituted with C, if the 11th position is substituted with another amino acid, it is preferably substituted with C, if the 12th position is substituted with another amino acid, it is preferably substituted with V, I, Z, T, R, or C, more preferably with V, I, Z, or R, most preferably with V or I, the 13th position is unsubstituted, and if the 14th position is substituted with another amino acid, it is preferably G, A, Y, X, S, T, Q, H, D, E, or C, The compound according to claim 3, more preferably substituted with G, A, S, T, Q, H, D, E, or C, more more preferably with G, H, D, or E, and most preferably with E, and if the 15th position is substituted with another amino acid, it is more preferably substituted with A, V, I, L, Z, Q, H, R, E, P, or C, more more preferably with A, V, I, L, Q, E, or P, more more preferably with I, L, Q, or E, and most preferably with I or L, the substitution with X represents a substitution with 3,4-dihydroxyphenylalanine, and the substitution with Z represents a substitution with pentafluorophenylalanine.

5. The compound according to claim 4, wherein the substitution in the peptide is made only at positions 2, 3, 4, 5, 6, 7, 9, 12, 14, or 15, preferably only at positions 2, 3, 5, 6, 7, 12, 14, or 15, more preferably only at positions 5, 12, or 14, and most preferably only at position 12 or 14.

6. The linker contains 1 to 12 optionally substituted skeletal atoms selected from carbon, nitrogen, oxygen, and sulfur, where the optional substitutions are =O, halogen, C1-4 hydrocarbon, C1-4 acyl, C1-4 alkoxy, -C(=O)-oligopeptide, -SH, -S-(C1-4 hydrocarbon), -NH ２ -NH- (C1-4 hydrocarbons), -NH- (C1-4 acyls), -N- (C1-4 hydrocarbons) ２ , -N- (C1-4 acyl) ２ The compound according to any one of claims 1 to 5, which may be an amino acid side chain or a targeted moiety.

7. Linker is of the general type (L1): 【Chemistry 2】 It has, During the ceremony, Aa is H, -NH ２ , -COOH, -CONH ２ , - (AA) ｎ -X', -C(=O)(AA) ｎ -X', or a dimerizing linker, Q is CH ２ , O, S or NH, AA is an amino acid residue that is independently selected in each case. X' is OH or NH ２ and The compound according to any one of claims 1 to 5, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

8. Linker is of the general type (L2): 【Transformation 3】 It has, During the ceremony, X' is OH or NH ２ And, Q is CH ２ , O, S or NH, SCh is an amino acid side chain, AA is an amino acid residue that is independently selected in each case. The compound according to any one of claims 1 to 5, wherein n is 1, 2, 3, 4, or 5.

9. Linker is of the general type (L3): 【Chemistry 4】 It has, During the ceremony, X' is OH or NH ２ And, Q is CH ２ , O, S or NH, yf is either H or OH, AA is an amino acid residue that is independently selected in each case. The compound according to any one of claims 1 to 5, wherein n is 1, 2, or 3.

10. The compound according to any one of claims 1 to 5, wherein the linker has a general formula selected from (L4a) to (L4h). Table 1

11. The peptide is an oligopeptide having 13 to 17 amino acid residues. The first amino acid is arginine, histidine, or lysine, preferably arginine. The seventh amino acid is isoleucine or leucine, preferably isoleucine. The twelfth amino acid is isoleucine or leucine, preferably leucine. The compound according to any one of claims 1 to 5.

12. The compound according to claim 1 or 2, wherein the peptide comprises a sequence represented by any one of SEQ ID NOs: 1 to 30, and up to six positions may be substituted by other amino acids.

13. The peptide has 15 amino acid residues, and / or The peptide comprises a sequence represented by one of SEQ ID NOs: 1 to 2, and / or The linker has one of the general formulas (L4a) to (L4h), and / or X is NH, The compound according to claim 1 or 2.

14. The compound according to claim 1, which is cyclic peptide 1 or a salt thereof. 【Transformation 5】

15. The compound according to claim 1, wherein the peptide is an oligopeptide represented by any one of SEQ ID NOs: 1, 33 to 102.

16. A composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.

17. The composition according to claim 16, which is a pharmaceutical composition.

18. The composition according to claim 17, wherein the pharmaceutical composition is for treating a viral infection.

19. The composition according to claim 18, wherein the viral infection is a coronavirus infection.

20. The composition according to claim 18, wherein the viral infection is SARS-CoV-2 infection.

21. An in vitro or ex vivo method for regulating the conformational dynamics of a viral spike protein, comprising the step of contacting the viral spike protein with a compound according to any one of claims 1 to 5.

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